Previous epidemiologic and experimental evidence suggesting a possible association between antidepressant drugs and the risk of breast cancer have several methodological weaknesses. The broad objective of this study is to investigate this association while addressing the flaws in previous studies. The primary hypothesis is that antidepressants increase the risk of breast cancer. This is a population-based case-control study. The 55-74 year-old cases to be selected from the Florida State Cancer Registry will be 400 breast cancer cases (ICD-9 code 174), diagnosed between 1/1/97 and 12/31/00, or the latest month in 2001 for which data are complete. The controls will be 400 female Orange County residents, and will be selected from Florida State Drivers' License files. They will be frequency-matched with cases on race and age (5-year intervals). Telephone interviews will be conducted by trained interviewers to collect data on past use of antidepressants, depression history and many potential confounders, using a Structured Questionnaire and the Diagnostic Interview Schedule (DIS). The data will be analyzed by means of unconditional logistic regression analysis. Odds ratios (ORs) and 95% CIs will be reported for breast cancer risk associated with antidepressant use, and will be adjusted for age, race, family history of breast cancer, alcohol, and other potential confounders. Additional analyses will include analysis stratified by depression status, dose-response analysis, and analysis for interactions between antidepressants and each of: depression, family history of breast cancer, history of benign breast disease and reproductive history. The results will be discussed in terms of implications for future use of antidepressants.